Cannabinoid formulations

ABSTRACT

The present invention provides stable, fast-acting liposomal and micelle formulations of cannabinoids that are suitable for pharmaceutical and nutraceutical applications.

This application is a Divisional Application of U.S. patent applicationSer. No. 13/547,039, filed Jul. 11, 2012, which claims priority to U.S.Provisional Application No. 61/506,331, filed on Jul. 11, 2011. Thecontents of all priority applications are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to liposomal and micelle formulations ofcannabinoids suitable for pharmaceutical and nutraceutical applications.

BACKGROUND OF THE INVENTION

Cannabinoids are compounds derived from Cannabis sativa, an annual plantin the Cannabaceae family. The plant contains about 60 cannabinoids. Themost active naturally occurring cannabinoid is tetrahydrocannabinol(THC), which is used for the treatment of a wide range of medicalconditions, including glaucoma, AIDS wasting, neuropathic pain,treatment of spasticity associated with multiple sclerosis, fibromyalgiaand chemotherapy-induced nausea. Additionally, THC has been reported toexhibit a therapeutic effect in the treatment of allergies,inflammation, infection, epilepsy, depression, migraine, bipolardisorders, anxiety disorder, and drug dependency and withdrawalsyndromes. THC is particularly effective as an anti-emetic drug and isadministered to curb emesis, a common side effect accompanying the useof opioid analgesics and anaesthetics, highly active anti-retroviraltherapy and cancer chemotherapy.

Cannabinoids are lipophilic and potentially acid-labile compounds.Because of their hydrophobic nature, cannabinoids are poorly absorbedsystemically from oral dosage forms because of the poor dissolution ofcannabinoids in the aqueous environment of gastrointestinal tract. Oralformulations of cannabinoids, therefore, exhibit low bioavailability.

Δ⁹-tetrahydrocannabinol is prone to oxidation, Prolonged contact withair results in the gradual oxidation of Δ⁹-tetrahydrocannabinol tocannabinol (CBN). There are currently two oral formulations ofΔ⁹-tetrahydrocannabinol commercially available by prescription in theUnited States: Dronabinol, is available commercially as Marinol®™ softgelatin capsules and Namisol®™ is available as sublingual tablets, havebeen approved by the Food and Drug Administration (FDA) for the controlof nausea and vomiting associated with chemotherapy and for appetitestimulation in AIDS patients suffering from the wasting syndrome.Marinol®™ is formulated by dissolving Δ⁹-tetrahydrocannabinol in sesameoil to manufacture soft gelatin capsules suitable for oraladministration. Marinol®™ is expensive and gelatin capsules of Marinol®™exhibit full therapeutic potency approximately one hour following theiradministration.

Onset of therapeutic potency for Dronabinol is shorter, approximately0.5 to 1 hour after oral administration, with a peak therapeutic effectlasting for a time period of 2-4 hours post administration. However, theamount of Dronabinol reaching the blood stream by absorption through thedigestive system is only 10-20% of the administered dose. Fasting orfood deprivation may further decrease the rate of absorption ofDronabinol.

On the other hand, Namisol®™ has a rapid uptake through the sublingualmucosa. However, the tablet, has to be kept under the tongue for thetime it takes to dissolve and stimulates the flow of saliva. This makeit difficult for patients to avoid swallowing the tablet whensubstantial amounts of saliva are produced.

Oral formulations of synthetic cannabionoids are also availablecommercially. For instance, Nabilone is a synthetic cannabinoid marketedas Cesamet® in Canada the United States, the United Kingdom and Mexico.Nabilone is formulated as capsules suitable for oral administration.Cesamet® is approved for use as an antiemetic and analgesic forneuropathic pain. Sativex®, is a mouth spray containingtetrahydrocannabinol (THC) and cannabidiol (CBD). It is approved for thetreatment of spasticity due to multiple sclerosis. Administration ofsynthetic cannabinoid formulations show fewer undesirable side effectsthan THC.

Because of their poor absorbtion and poor bioavailability, oralformulations have the additional disadvantage that they require severaladministrations a day, making it inconvenient for patients who havedifficulty swallowing.

Accordingly, there is an urgent need in the art for oral formulations ofcannabinoids with improved dissolution and taste and enhancedbioavailability and absorption, while at the same time do not causegastrointestinal irritation. The present invention satisfies this need.

SUMMARY OF THE INVENTION

It is therefore an object of the invention to provide solutions to theaforementioned deficiencies in the art. To this end the inventionprovides a stable, aqueous micelle suspension of one or morecannabinoids or cannabinoid analogues, wherein the stable aqueousmicelle suspension of one or more cannabinoids or cannabinoid analoguesdoes not comprise phospholipids and cholesterol. For the inventivecompositions, the average micelle diameter size is in a range between 50and 1000 nm.

According to one embodiment, the final maximum concentration ofcannabinoids or cannabinoid analogues in the aqueous micelle suspensionof one or more cannabinoids or cannabinoid analogues is 2 g/liter. Thecannabinoids or cannabinoid analogues are a natural compound, asynthetic compound, a semi-synthetic compound, or mixtures thereof.Illustrative of cannabinoids or cannabinoid analogues are compoundsselected from the group consisting of cannabinol, cannabidiol,Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabinol,11-hydroxy-tetrahydrocannabinol, 11-bydroxy-Δ9-tetrahydrocannabinol,levonantradol, Δ11-tetrahydrocannabinol, tetranydrocannabinol,tetrahydrocannabivarin, dronabinol, amandamide, nabilone, a combinationthereof, a natural or synthetic analogue thereof, and a natural orsynthetic molecule with a basic cannabinoid structure.

In one embodiment the stable aqueous micelle suspension of one or morecannabinoids or cannabinoid analogues further comprises a stabilizerselected from the group consisting of guar gum, xyanthan gum cellulosehyaluronic acid, polyvinyl pyrrolidone (PVP), alginate, chondritinsulfate, poly gamma glutamic acid, gelatin, chitisin, corn starch andflour, in an amount from about 0.25% to about 2% (w/v).

In yet another embodiment is provided a method of producing a stableaqueous micelle suspension of one or more cannabinoids or cannabinoidanalogues that is devoid of phospholipids and cholesterol. The inventivemethod comprises the steps of (a) dissolving one or more cannabinoids orcannabinoid analogues in ethanol to obtain an ethanol cannabinoidsolution; (b) injecting the ethanol cannabinoid solution into distilledwater to obtain a micelle cannabinoid aqueous suspension; and (c)removing the ethanol from the cannabinoid aqueous suspension therebyproducing a stable aqueous micelle suspension of one or morecannabinoids or cannabinoid analogues. The aqueous micelle suspension donot contain phospholipids and cholesterol and are devoid of an aqueouscore under oil immersion microscopy.

According to one embodiment, the average micelle diameter size in theaqueous micelle suspension of one or more cannabinoids or cannabinoidanalogues is in a range between 50 and 1000 nm, and the final maximumconcentration of cannabinoids or cannabinoid analogues in the aqueousmicelle suspension of one or more cannabinoids or cannabinoid analoguesis 2 g/liter. The one or more cannabinoids or cannabinoid analogues ofthe present invention are a natural compound, a synthetic compound, asemi-synthetic compound, or mixtures thereof. Illustrative of suchcompounds are cannabinoids or cannabinoid analogues selected from thegroup consisting of cannabinol, cannabidiol, Δ9-tetrahydrocannabinol,Δ8-tetrahydrocannabinol, hydroxy-tetrahydrocannabinol,11-hydroxy-Δ9-tetrahydrocannabinol, levonantradol,Δ11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,amandamide, nabilone, a combination thereof, a natural or syntheticanalogue thereof, and a natural or synthetic molecule with a basiccannabinoid structure.

The present invention in one of its embodiments provides a highlyconcentrated liposomal formulation of one or more cannabinoids orcannabinoid analogues, with final maximum concentrationd of cannabinoidsor cannabinoid analogues in the liposomal suspension being 50 g/liter.The one or more cannabinoids or cannabinoid analogues in the inventivecomposition are a natural compound, a synthetic compound, asemi-synthetic compound, or mixtures thereof. Illustrative of suchcompounds are cannabinoids or cannabinoid analogues selected from thegroup consisting of cannabinol, cannabidiol, Δ9-tetrahydrocannabinol,Δ8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol,11-hydroxy-Δ9-tetrahydrocannabinol, levonantradol,Δ11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,amandamide, nabilone, a combination thereof, a natural or syntheticanalogue thereof, and a natural or synthetic molecule with a basiccannabinoid structure.

The average diameter size of liposomes in the inventive composition isfrom about 200 to about 400 nm. For these compositions the maximumphospholipid content of the hydrophobic/lipophilic membrane is 50% ofthe total composition and the hydrophobic/lipophilic membrane comprisesabout 26% phosphatidylcholine, about 10% phosphatidylethanolamine, about13% phosphonophospholipids, and about 1% of other phospholipids.

Also provided as an embodiment of the present technology is a method ofproducing a stable, highly concentrated liposomal formulation of one ormore cannabinoids or cannabinoid analogues by (a) dissolving one or morecannabinoids or cannabinoid analogues in ethanol to obtain an ethanolcannabinoid solution; (b) adding a phospholipid to the ethanolcannabinoid solution to obtain an ethanol-phospholipid cannabinoidsolution; (c) injecting the ethanol-phospholipid cannabinoid solutioninto distilled water to obtain a liposomal cannabinoid suspension; and(d) removing the ethanol from the liposomal cannabinoid suspension,thereby producing a stable liposomal suspension of one or morecannabinoids or cannabinoid analogues;

The final maximum concentration of cannabinoids or cannabinoid analoguesin the liposomal suspension is 50 g/liter and the one or morecannabinoids or cannabinoid analogues are a natural compound, asynthetic compound, a semi-synthetic compound, or mixtures thereof.Preferably the cannabinoids or cannabinoid analogues are selected fromthe group consisting of cannabinol, cannabidiol,Δ9-tetrahydrocannabinol, Δ8-tetrahydrocannabinol,11-hydroxy-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol,levonantradol, Δ11-tetrahydrocannabinol, tetrahydrocannabinol,tetrahydrocannabivarin, dronabinol, amandamide, nabilone, a combinationthereof, a natural or synthetic analogue thereof, and a natural orsynthetic molecule with a basic cannabinoid structure.

The inventive method further comprises the step of adding sodiumalginate to the liposomal suspension of one or more cannabinoids orcannabinoid analogues to obtain an alginate liposomal cannabinoidsuspension that has a final alginate concentration of 2% w/v, followedby the addition of calcium chloride to the alginate liposomalcannabinoid suspension to obtain a calcium alginate-encapsulatedliposomal cannabinoid suspension. This suspension is then cold-pressedand air-dried to remove the water so as to obtain a dry cannabinoidpowder. The dry cannabinoid powder can be re-suspended in citrate bufferto obtain an aqueous cannabinoid solution. The amount of cannabinoid orcannabinoid analogue in the aqueous cannabinoid solution is greater than40%.

According to an embodiment of the inventive method, sodium alginate isadded to the liposomal suspension of one or more cannabinoids orcannabinoid analogues to obtain an alginate liposomal cannabinoidsuspension that has a final alginate concentration of 4% w/v.Shell-freezing of this solution using dry ice or in acetone bath andfreeze-drying to remove water provides a dry cannabinoid powder that ismilled and can be re-suspended in water to obtain an aqueous cannabinoidsolution. The amount of cannabinoid or cannabinoid analogue in theaqueous cannabinoid solution is greater than 40%.

In one embodiment, L-leucine and a sugar are added to the liposomalsuspension of one or more cannabinoids or cannabinoid analogues toobtain a sugar liposomal cannabinoid suspension The sugar is selectedfrom the group consisting of lactose and sucrose. Shell-freezing thesugar liposomal cannabinoid suspension over dry ice acetone bath andfreeze-drying the suspension to remove the water provides a drycannabinoid powder that is milled and can be re-suspended in water toobtain an aqueous cannabinoid solution. The amount of cannabinoids orcannabinoid analogues in the aqueous solution is 50 g/liter.

Such an aqueous cannabinoid solution can be in the form of a fast-actingpharmaceutical composition, a nutraceutical composition, or a food orbeverage for administration to a subject. Illustrative of foodcontaining the aqueous cannabinoid solution are foods selected from asoup, a baking good, a dairy product, a meat product, a fish product, avegetable product or a fruit product. The aqueous cannabinoid solutionformulated as pharmaceutical composition, a nutraceutical composition,or a food or beverage are fast-acting formulations for oral, enteral,parenteral, intravenous, pulmonary, mucosal, sub-mucosal or topicaladministration.

In yet another embodiment, the invention provides a method ofalleviating pain or reducing undesirable side effects associated withradiation therapy or chemotherapy in a subject in need thereofcomprising administering to the subject the aqueous cannabinoid solutionas described above. Subjects treated using the inventive method have acompromised immune system, a cancer, a pulmonary disease or a conditionthat causes violent tremors.

The foregoing general description and following brief description of thedrawings and the detailed description are exemplary and explanatory andare intended to provide further explanation of the invention as claimed.Other objects, advantages, and novel features will be readily apparentto those skilled in the art from the following detailed description ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides an oil immersion image of a micelle suspension stainedwith fast blue as seen through a red filter.

FIG. 2 provides an oil immersion image of an unstained liposomalsuspension.

FIG. 3 provides an oil immersion image of a liposomal suspension stainedwith fast blue as seen through a red filter. The stain condensates onthe outer liposome membrane.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides stable, fast-acting formulation of acannabinoid or a cannabinoid analog. The term “analog” refers tocompound that is structurally related to naturally occurringcannabinoids, but whose chemical and biological properties may differfrom naturally occurring cannabinoids. In the present context, analog oranalogs refer compounds that may not exhibit one or more unwanted sideeffects of a naturally occurring cannabinoid. Analog also refers to acompound that is derived from a naturally occurring cannabinoid bychemical, biological or a semi-synthetic transformation of the naturallyoccurring cannabinoid. According to one aspect, therefore, are providedliquid compositions of cannabinoids and their analogs. The presentinvention also provides stable colloidal formulations that aremanufactured by contacting a solution containing a cannabinoid, itsanalog, or both into a solvent such as water, with or withoutpharmaceutically acceptatable buffers. Any solvent such as C1-C₆aliphatic alcohols or mixtures of water and alcohols, acetone or anywater miscible organic solvent can be used to dissolve the cannabinoids.

The inventive cannabinoid formulations are in the form of micelles orliposomes that encapsulate a cannabinoid or its analog within themembrane of the micelles or liposomes. Within the context of the presenttechnology, the term “micelle” refers to an aggregate of surfactantmolecules dispersed in a liquid colloid, while “liposome” refers to avesicle composed of a mono or bilayer lipid.

Other drugs, and pharmaceutically acceptable carriers if present, may bein the lipophilic membrane or entrapped in the aqueous fluid that formsthe core of the liposome. The entrapped cannabinoids contribute to thestability of the micelle/liposome membranes, such that themicelle/liposomes formulations may be used as an improved, fast,reliable and efficient system for the oral, enteral, parenteral,intravenous or topical delivery of cannabinoids and/or additional drugsto subjects in need thereof. The term “subject” refers to a mammal inneed of treatment or undergoing treatment using the inventivecompositions. Mammalian subjects include without limitation humans, dog,cat, horse or any other animal in need of treatment.

Unilamellar micelles or liposomes that are thermostable at temperaturesgreater than 50° C. are used in the manufacture of cannabinoidformulations according to the present invention. These micelles orliposomes are obtained by contacting a solution of a cannabinoid, itsanalog or both (a cannabinoid extract), with an aqueous solvent or anaqueous solution of a pharmaceutically active compound or drug. Themixing of the cannabinoid solution occurs in a manner suitable for therapid dissolution of the cannabinoid solution in the aqueous solution.This can be accomplished through a variety of means including dilution,injection through a small orifice under pressure, and ultrasonicatomization.

For certain embodiments, the inventive composition is in the form of aconcentrated, stable colloidal suspension that is obtained by infusing asolvent solution containing the cannabinoid extract or pure cannabinoidsinto a solvent such as water, with or without buffer. Stabilizing agent,for instance, a polymer or compounds selected from cellulose hyaluronicacid, polyvinyl pyrrolidone (PVP), alginate, chondritin sulfate, polygamma glutamic acid, gelatin, chitisin, corn starch and flour can beused to stabilize the micelle formulations.

Typically, the size of the inventive micelles is from about 0.01 μm toabout 2.0 μm. For certain embodiments, the size of the sphericalmicelles is about 0.05 μm, about 0.1 μm, about 0.15 μm, 0.2 μm, 0.25 μm,0.3 μm, 0.35 μm, 0.4 μm, 0.45 μm, 0.5 μm, 0.55 μm, 0.6 μm, 0.7 μm, 0.75μm, 0.8 μm, 0.85 μm, 0.9 μm, about 0.95 μm, about 1.0 μm, 1.20 μm, 1.40μm, 1.50 μm, 1.60 μm, 1.70 μm, 1.80 μm, 1.90 μm and 2.0 μm. For certainembodiments, micelles that are about 0.04 μm, about 0.05 μm, about 0.06μm, about 0.07 μm, about 0.08 μm, or about 0.09 μm are used to formulatethe inventive compositions.

According to one aspect, the maximum final concentration of acannabinoids or an analog of the cannabinoid in the micellar colloidalsuspension is from about 1.0 mg/mL to about 10.0 mg/mL both valuesinclusive. For some embodiments, the concentration of a cannabinoidextract within the inventive micelles is about 1.0 mg/mL, about 2.0mg/mL, about 3.0 mg/mL, 4.0 mg/mL, about 5.0 mg/mL, about 6.0 mg/mL,about 7.0 mg/mL, about 8.0 mg/mL, or about 9.0 mg/mL.

Typical concentrations of cannabinoids within a liposomal suspensionaccording to the present invention are about 50 mg/mL. For certainembodiments, the maximum final concentration of cannabinoids or ananalog of the cannabinoid in the liposomal formulation is from about10.0 mg/mL to about 300.0 mg/mL both values inclusive, for example,about 15.0 mg/mL, about 20.0 mg/mL, about 30.0 mg/mL, about 40.0 mg/mL,about 50.0 mg/mL, about 60.0 mg/mL, about 70.0 mg/mL, about 80.0 mg/mL,about 90.0 mg/mL, about 150.0 mg/mL, about 200.0 mg/mL, about 250.0mg/mL, or about 300.0 mg/mL.

For liposomal compositions according to this invention, the size of theunilamellar spherical liposome is from about 0.1 μm to about 2.0 μm bothvalues inclusive, such as about 0.15 μm, about 0.2 μm, about 0.22 μm,about 0.25 μm, about 0.3 μm, about 0.32 μm, about 0.35 μm, about 0.4 μm,about 0.42 μm, about 0.45 μm, about 0.5 μm, about 0.52 μm, about 0.55μm, about 0.6 μm, about 0.7 μm, about 0.75 μm, about 0.8 μm, about 0.85μm, about 0.9 μm, about 0.95 μm, about 1.0 μm, about 1.1 μm, about 1.2μm, about 1.3 μm, about 1.4 μm, about 1.5 μm, about 1.6 μm, about 1.7μm, about 1.8 μm, about 1.9 μm, or about 2.0 μm.

The formulations of the invention are therefore particularly suitablefor oral administration and may be administered to subjects with apre-existing condition or pre-disposed to certain disease conditions,acute pain, or chronic pain conditions. Conditions contemplated by theinvention include, but are not limited to, gastrointestinal, metabolic,neurological, circulatory, soft tissue, musculoskeletal, chronic oracute pain, nausea, decreased appetite, skin disorders, sexualdysfunction, glaucoma, AIDS wasting, neuropathic pain, treatment ofspasticity associated with multiple sclerosis, fibromyalgia,chemotherapy-induced nausea, allergies, inflammation, infection,epilepsy, depression, migraine, bipolar disorders, anxiety disorder,dependency and withdrawal. In addition, the methods of the invention maybe used to alleviate or relief symptoms or side effects associated withanti-retroviral therapy, chemotherapy and radiation therapy.

Illustrative of cannabinoid compounds include without limitationcannabinol, cannabidiol, Δ9-tetrahydrocannabinol,Δ8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol,11-hydroxy-Δ9-tetrahydrocannabinol, levonantradol,Δ11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,amandamide, nabilone, any combination thereof, any natural or syntheticmodification thereof, or any natural or synthetic molecule with a basiccannabinoid structure. In a preferred embodiment, the cannabinoid istetrahydrocannabinol (THC).

Natural cannabinoid compounds used in the inventive compositions arereadily obtained from plant tissue, for example, trichones of the C.sativa plant, by suspending the tissue in an appropriate solvent toextract cannabinoid compounds and other tissue components. Analyticalpurification of such an extract provides pharmaceutical gradecannabinoid compounds. Alternatively, cannabinoid compounds areextracted from plant tissue under supercritical conditions. Solventsused for supercritical extraction of cannabinoids include withoutlimitation carbon dioxide, or other gases in isolation or combinationwith or without solvent modifiers, selected from ethanol, propanol,butanol, hexane, chloroform, dichloromethane, acetone, or any organicsolvent capable of extracting cannabinoids, and alcohol-water mixtures,for instance water-ethanol or water-butanol mixtures.

In addition to natural cannabinoids, the present technology encompassessynthetic cannabinoid compounds as well as cannabinoids and theiranalogs that are obtained using semi-synthetic protocols. Themanufacture of cannabinoid compounds and their analogs usingsemi-synthetic means involves contacting an appropriate substrate withone of the cannabinoid synthase enzymes. For instance,tetrahydrocannabinolic acid (THCA) or its analogs can be manufacturedsemi-synthetically by contacting cannabigerolic acid (CBGA) or anappropriately substituted derivative of CBGA with THC synthase to obtainthe corresponding THCA or THCA analog respectively. The inventivecompositions may also contain natural or synthetically modifiedcannabinoids.

The inventive compositions have unexpected advantageous properties. Forinstance, micellar and liposomal compositions according to the presentinvention are stable at high temperatures, exceeding 50° C., are stableto sonication, capable of carrying large payloads of cannabinoids aswell as other drug suitable for use in combination therapy and can bestored for extended periods of time, for example greater than 20 weeksat 25° C.

The inventive compositions also exhibit superior systemic delivery andrelease of cannabinoids from the micelle or liposomes used in themanufacture of the inventive composition. The release of a cannabinoidfrom a liposome or micelle of the inventive composition can be modulatedby changing the ratio of the concentration of lipid to the concentrationof cannabinoid present in the liposome.

In one embodiment, tissue specific delivery can be achieved by modifyingthe surface of the liposomes or micelles with compounds that bindspecifically to biological macromolecules expressed on cellularsurfaces. For instance, the micelle or liposomal surface can bederivatized to display an antibody specific to an antigen expressed oncancer cells.

According to one embodiment, compositions of the present invention areused in the treatment of disease conditions. For instance, an inventivecomposition of the cannabinoid extract, (cannabinoid, an analog of acannabinoid, or both), can be administered to a patient or subject inneed of treatment either alone or in combination with othercompounds/drugs having similar or different biological activities.

For example, compositions of the invention may be administered in acombination therapy, i.e., either simultaneously in single or separatedosage forms or in separate dosage forms within hours or days of eachother. Examples of compounds/drugs used in such combination therapiesinclude without limitation, chemotherapeutic agents, immunosuppressiveagents, immunostimulatory, anti pyretic, cytokines, opioids, cytokines,cytotoxic agents, nucleolytic compounds, radioactive isotopes,receptors, pro-drug activating enzymes, which may be naturally occurringor produced by recombinant methods, anti-inflammatory agents,antibiotics, protease inhibitors, growth factors, osteo-inductivefactors and the like.

In some embodiments, the composition further contains, in accordancewith accepted practices of pharmaceutical compounding, one or morepharmaceutically acceptable excipients, diluents, adjuvants,stabilizers, emulsifiers, preservatives, colorants, buffers, flavorimparting agents. As stated above, the inventive compositions maycontain a cannabinoid, an analog of a cannabinoid, or both and may beconsumed directly or formulated into nutraceutical or pharmaceuticallyacceptable compositions suitable for oral, enteral, parenteral,intravenous or topical administration.

The term parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques. Such excipients are well known in the art. Dosage forms fororal administration include food, beverages, drinks, soups, baked goods,syrups, oral pharmaceutical compositions, nutraceutical formulations,and the like. Suitable pharmaceutical carriers include any suchmaterials known in the art, e.g., any liquid, gel, solvent, liquiddiluent, solubilizer, polymer or the like, which is non-toxic and whichdoes not significantly interact with other components of theformulations in a deleterious manner.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, solutions, suspensions,syrups and elixirs. In addition to the cannabinoid extract, the liquiddosage forms can contain inert diluents commonly used in the art. Forinstance, liquid formulations can contain water, alcohol, polyethyleneglycol ethers, or any other pharmaceutically acceptable solvents.Solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide,oils (in particular, cottonseed, groundnut, corn, germ, olive, castor,and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof may alsobe present in the inventive compositions. Additionally, oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Whenformulated as a suspension, the inventive compositions contain thecannabinoid extract and suspending agents, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol, sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, tragacanth, and mixtures thereof.

Solid dosage forms suitable for oral administration include, capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecannabinoid extract, for instance, a cannabinoid or a cannabinoid analogcan be used alone or in combination with one or more drugs are mixedwith at least one pharmaceutically acceptable excipient or carrier suchas sodium citrate or dicalcium phosphate and/or a) fillers or extenderssuch as starches, lactose, sucrose, glucose, mannitol, and silicic acid,b) binders such as, for example, carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants suchas glycerol, d) disintegrating agents such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate, e) solution retarding agents such as paraffin, f)absorption accelerators such as quaternary ammonium compounds, g)wetting agents such as, for example, acetyl alcohol and glycerolmonostearate, h) absorbents such as kaolin and bentonite clay, and i)lubricants such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Forcapsules, tablets and pills, the dosage form can also comprise bufferingagents.

Micellular or liposomal suspensions can be encapsulated with a varietyof polymers, sugars, and chelating agents, to yield stable solidliposomal cannabinoid preparation. Encapsulation can take the form ofcross linked polymers, trapping of the micells or liposomes within a noncrosslinked polymer network, or dispersed within the crystallinestructer of sugar starches or protein molecules. These granulas can befurther process to yield sublingual films, suppositories, dispersablepowder, tablets, gel capsules, etc.

Solid dosages in the form of tablets, dragees, capsules, pills, andgranules can be coated using compounds that accelerate or decrease therelease of cannabinoids. For instance, the invention encompases soliddosage forms having enteric coatings, extended-release coatings,sustained-release coatings, delayed release coatings andimmediate-release coatings. Methods used to coat solid dosage forms aswell as the materials used to manufacture such coatings are well knownin the pharmaceutical formulary art. The solid dosage forms canoptionally contain opacity enhancing agents. According to an embodiment,the solid dosage form comprises an enteric coating that permits therelease of a cannabinoid or cannabinoid analog alone or in combinationwith one or more drugs at a specific location within thegastrointestinal tract, optionally, in a delayed manner. Exemplary ofsuch coating materials include glyceryl monostearate or glyceryldistearate may be employed, polymeric substances and waxes. Thecannabinoid extract, for instance, a cannabinoid or cannabinoid analogalone or in combination with one or more drugs can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

A dietary composition according to the present invention is anyingestible preparation that contains the cannabinoid suspensions of theinvention mixed with a food product. The food product can be dried,cooked, boiled, lyophilized or baked. Breads, teas, soups, cereals,salads, sandwiches, sprouts, vegetables, animal feed, pills and tablets,are among the vast number of different food products contemplated in thepresent invention.

Compositions for parenteral injection comprise pharmaceuticallyacceptable sterile aqueous or nonaqueous solutions, dispersions,suspensions or emulsions as well as sterile powders for reconstitutioninto sterile injectable solutions or dispersions prior to use. Examplesof suitable aqueous and nonaqueous carriers, diluents, solvents orvehicles include water, ethanol, polyols (such as glycerol, propyleneglycol, polyethylene glycol, and the like), carboxymethylcellulose andsuitable mixtures thereof, vegetable oils (such as olive oil), andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants. The compositions of thepresent invention can also contain adjuvants such as, but not limitedto, preservatives, wetting agents, emulsifying agents, and dispersingagents. Compositions for parenteral delivery generally include isotonicagents such as sugars, sodium chloride, and the like. Prolongedabsorption of the injectable pharmaceutical formulation can be broughtabout by the inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable medium just prior to use.

Dosage forms for topical administration include, but are not limited to,ointments, creams, emulsions, lotions, gels, sunscreens and agents thatfavor penetration within the epidermis. Various additives, known tothose skilled in the art, may be included in the topical formulations ofthe invention. Examples of additives include, but are not limited to,solubilizers, skin permeation enhancers, preservatives (e.g.,anti-oxidants), moisturizers, gelling agents, buffering agents,surfactants, emulsifiers, emollients, thickening agents, stabilizers,humectants, dispersing agents and pharmaceutical carriers. Examples ofmoisturizers include jojoba oil and evening primrose oil. Suitable skinpermeation enhancers are well known in the art and include loweralkanols, such as methanol ethanol and 2-propanol; alkyl methylsulfoxides such as dimethylsulfoxide (DMSO), decylmethylsulfoxide (C10MSO) and tetradecylmethyl sulfoxide; pyrrolidones, urea;N,N-diethyl-m-toluamide; C2-C6 alkanediols; dimethyl formamide (DMF),N,N-dimethylacetamide (DMA) and tetrahydrofurfuryl alcohol. Examples ofsolubilizers include, but are not limited to, hydrophilic ethers such asdiethylene glycol monoethyl ether (ethoxydiglycol, availablecommercially as Transcutol®) and diethylene glycol monoethyl etheroleate (available commercially as Softcutol®); polyoxy 35 castor oil,polyoxy 40 hydrogenated castor oil, polyethylene glycol (PEG),particularly low molecular weight PEGs, such as PEG 300 and PEG 400, andpolyethylene glycol derivatives such as PEG-8 caprylic/capric glycerides(available commercially as Labrasol®); alkyl methyl sulfoxides, such asDMSO; pyrrolidones, DMA, and mixtures thereof.

Prevention and/or treatment of infections can be achieved by theinclusion of antibiotics, as well as various antibacterial andantifungal agents, for example, paraben, chlorobutanol, phenol sorbicacid, and the like, in the compositions of the invention.

One of ordinary skill will appreciate that effective amounts of theagents in the compositions used in the methods of the invention can bedetermined empirically. It will be understood that, when administered toa human patient, the total daily usage of the composition of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factors:the type and degree of the response to be achieved; the activity of thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the duration of the treatment; drugs used incombination or coincidental with the method of the invention; and likefactors well known in the medical arts.

The potential commercial uses of the disclosed preparations include, forexample, protective/prophylactic and medical uses. The compositions ofthe invention can also be administered by a variety of other routes,including mucosal, subcutaneous and intramuscular administration, andmay comprise a variety of carriers or excipients known in the formularyart, such as, non-toxic solid, semisolid or liquid filler, diluent,encapsulating material and formulation auxiliaries that arepharmaceutically acceptable.

The present invention thus generally described, will be understood morereadily by reference to the following examples, which are provided byway of illustration only, and are not intended to be limiting thepresent invention.

EXAMPLES A. General Protocol for the Manufacture of Micelles

A cannabinoid, its analog or cannabinoid extract are dissolved in awater miscible organic solvent. This solvent cannabinoid solution israpidly mixed or injected into an appropriate aqueous environment. Therapid dissolution of the organic solvent causes the dissolvedcannabinoids to self align into micro or nano micellar particles. Size,composition and concentration of the micells are controlled by thechemical properties of the cannabinoids, the organic solvent/aqueousenvironment and the physical parameters of the solvent addition.

B. General Protocol for the Manufacture of Liposomes

Pure Cannabinoids or cannabinoid extracts are dissolved in a watermiscible organic solvent. To this solution various amphipathic moleculessuch as phospholipids, sterols, and/or fatty acids are also dissolved.This solution containing the cannabinoids and amphipathic molecules israpidly mixed or injected into an appropriate aqueous environment. Therapid dissolution of the organic solvent causes the dissolvedcannabinoids and amphipathic molecules initiates the spontaneousformation of ordered lipid layers which self assemble into micro or nanoliposomal particles. The size, composition and concentration of theliposomes are controlled by the chemical properties and relativeconcentrations of the cannabinoids and lipids, the organicsolvent/aqueous environment and the physical parameters of the solventaddition.

In an exemplary composition, the hydrophobic/lipophilic membranecomprises about 40% phosphatidylcholine, about 3.5%phosphatidylethanolamine, about 6% phosphonophospholipids, and about0.5% of other phospholipids. According to another embodiment, Accordingto another embodiment the hydrophobic/lipophilic membrane of liposomesin the inventive composition comprises about 26% phosphatidylcholine,about 10% phosphatidylethanolamine, about 13% phosphonophospholipids,and about 1% of other phospholipids.

C. General Protocol for Encapsulation of Micelles or Liposomes

To a liposomal or micellular suspension, a polymer or encapsulatingmatrix is added to a desired concentration. If so desired a crosslinking agent can be added. The polymer liposomal mixture is thendehydrated through various means, such as filtration, evaporation,freeze drying, or spray drying. The dehydrated encapsulant or film canbe further milled to a desired average particle size.

The present invention uses micelles and liposomes as vehicles fordelivery a cannabinoid, its analog, or both to a subject in need oftreatment. The micelles and liposomes containing a cannabinoid, itsanalog, or both are dispersed in a pharmaceutically acceptable solventthat is suitable for a specific route of delivery to a subject in needof treatment. The inventive micellar or liposomal formulations canreadily be manufactured by methods further described herein.

I. Micelle Formulation Example 1 1 g/L Micelle Suspension of aCannabinoid without Stabilizer

Cannabinoids were obtained from plant tissue by supercritical fluidextraction (SFE). Supercritical carbon dioxide was used as theextractant. Briefly, the plant material was contacted with carbondioxide maintained above the critical temperature and pressure, forexample, a temperature above 350 Kelvin (K) and a pressure above 150 barto extract cannabinoids from the tissue. This cannabinoid extract wasused to manufacture the inventive micellar compositions. Thecompositions manufactured using the protocol further described below hasno added stabilizers and can be stored as a stable aqueous suspensionfor 3 days at 25° C.

TABLE 1 Micelle Formulation Ethanol Injection Phospholipid Content NoneDrug Amount 850 mg Extract Drug Source 70% THC content Cannabis FlowerExtract obtained from supercritical CO2 extraction. Injection DrugConcentration 20 ml of 30 mg/ml THC in 95% Ethanol at 10° C. InjectionType 50 ml Syrnige w/ 22 gauge needle 50 psi 10 ml/min Aqueous Medium195 ml Distilled H20 at 25° C. Final Ethanol to Aqueous 1:10, ethanolremoved via rotor Ratio evaporation at 30 mmHg at less than 30 C.Encapsulation Efficiency >95% Maximum final drug 200 mls og 1 g/l THCconcentration in suspension External Stabilizer None MicellCharacterisation .2-1μ, no core apparent under oil oil immersion, stableat RT for 3 days

Thus, 850 mg of a 70% THC cannabis flower extract was dissolved in 95%ethanol (20 mL) and this solution was cooled to 10° C. prior to itsinjection under pressure (50 psi, 10 mL/min), into 195 mL, of distilledwater at 25° C. A 50 mL lurlock syringe equipped with a 22 gauge needlewas used to inject the cannabinoid solution into water. The resultantaqueous micelle suspension was subjected to rotary evaporation at areduced pressure of 30 mm mercury to remove ethanol. The temperature ofthe round bottom flask containing the aqueous micelle suspension wasmaintained below 30° C. The micelle formation efficiency using thisprotocol is greater than 95%. The final maximum concentration of THC inthe micelles is 1 g/L of the micelle suspension. Micelles obtained usingthis protocol were 0.2-1.0 μm in diameter and the aqueous micellesuspension was stable for 3 days at 25° C. No aqueous core was visibleunder oil immersion microscopy.

Example 2 1 g/L Micelle Suspension of THC with Stabilizer

TABLE 2 Micelle Formulation Ethanol Injection Phospholipid Content NoneDrug Amount 850 mg Extract Drug Source 70% THC content Cannabis FlowerExtract obtained from supercritical CO2 extraction. Injection DrugConcentration 20 ml of 30 mg/ml THC in 95% Ethanol at 25° C. InjectionType 50 ml Syrnige w/ 22 gauge needle 50 psi 10 ml/min Aqueous Medium195 ml Distilled H20 at 25° C. Final Ethanol to Aqueous 1:10, ethanolremoved via Ratio rotor evaporation at 30 mmHg at less than 30 C.Encapsulation Efficiency >95% Maximum final drug 200 mls og 1 g/l THCconcentration in suspension External Stabilizer 0.1% w/v Guar Gum addedin 10 mg portions Micell Characterisation .2-1μ, no core apparent underoil oil immersion, stable at RT for 7 days

The cannabinoids were obtained from plant tissue using supercriticalcarbon dioxide as the extractant. 850 mg of a 70% THC cannabis flowerextract was dissolved in 95% ethanol and brought to a final volume of 20mL using 95% EtOH. The resultant solution was cooled to 10° C. andinjected (50 psi, 10 mL/min), into 195 mL of distilled water (25° C.)using a 50 mL lurlock syringe equipped with a 22 gauge needle. Ethanolwas removed from the resultant aqueous suspension of the micelle byrotary evaporation under a reduced pressure of 30 mm Hg to keep thetemperature of this solution below 30° C. After removal of the ethanol,0.2 g, (0.1% w/v), guar gum was added in 10 mg portions. The micelleformation efficiency is >95%, with a final maximum THC concentration of1 g/L. The micelles obtained using this protocol were 0.2-1.0 μm indiameter and the aqueous micelle suspension was stable for 7 days at 25°C. No aqueous core was visible under oil immersion microscopy.

Micelles prepared according to this embodiment of the technology wereunilamellar, as confirmed by freeze fracture electron microscopy (datanot shown). As shown in FIG. 1, staining with a cannabinoid specific dye(Fast Blue) demonstrated that the membrane, and not the core of themicelles, stained with the dye. Moreover, the addition of the dye to thesuspension caused immediate precipitation of the micelles. These dataclearly demonstrated that the cannabinoid was entrapped in the membraneand not in the core of the micelles.

Example 3 2 g/L Micelle Suspension Using Synthesized Delta-9 THC(Dronabinol)

TABLE 3 Micelle Formulation Ethanol Injection Phospholipid Content NoneDrug Amount 420 mg D9 THC Drug Source Drobabinol from sigma (D9 THC)Injection Drug 20 ml of 21.0 mg/ml THC in Concentration 95% Ethanol at10° C. Injection Type 0.17 mm stainless steel orifice at 10 ml/min at300 psi Ethanol to Aqueous Ratio 195 ml Distilled H20 at 37° C. Ethanolto Aqueous 1:10, ethanol removed via rotor evaporation at 30 mmHg atless than 30 C. Encapsulation Efficiency >95% Maximum final drug 200 mlsof 2 g/l THC concentration in suspension External Stabilizer 0.1% GuarGum in 10 mg portions Characterizaton .1-.5μ, no core apparent un oilimmersion, stable a RT for 1 week

10.5 g Dronabinol was dissolved 95% ethanol (final volume 20 mL). Thesolution was cooled to 10° C. and injected through a 0.17 mm stainlesssteel orifice at 300 psi into 195 mL, of distilled water at 37° C. Theresultant aqueous suspension micelles was subjected to rotaryevaporation at 30 mm Hg to remove ethanol at a solution temperaturebelow 30° C. After removal of the ethanol, 0.2 g, (0.1% w/v), guar gumwas added in 10 mg portions. The micelle formation efficiency using thisprotocol was greater than 95% and the final concentration of THC was 2g/L. Micelles 0.1-0.5 μm in diameter were obtained and this aqueousmicelle suspension was stable for 7 days at 25° C. No aqueous core wasvisible under oil immersion microscopy.

Example 4 2 g/L Micelle Suspension using a Mixture of Cannabinoids

TABLE 4 Micelle Formulation Ethanol Injection Phospholipid Content NoneDrug Amount 200 mg THC, 110 mg CBD, 110 mg CBC Drug Source Synthsised InHouse Injection Drug Concentration 20 ml of 21.0 mg/ml Cannabinpoids in95% Ethanol at 25° C. Injection Type Ultrasonic Atomizer Nozzle @ 60 Hz,20 um drop size, 10 ml/min Aqueous Medium 195 ml PBS at 25° C. Ethanolto Aqueous Ratio 1:10, ethanol removed via rotor evaporation at 30 mmHgat less than 30 C. Encapsulation Efficiency >95% Maximum final drug 200mls of 1 g/L THC, 0.5 g/l CBD, concentration in suspension 0.5 g/l CBCExternal Stabilizer 0.1% Guar Gum in 10 mg portions Characterizaton50-200 nm, no core apparent un oil immersion, stable a RT for 4 weeks

200 mg of chemically synthesized THC was combined with 110 mg chemicallysynthesized CB and 110 mg synthetic CBC and the mixture was dissolved in95% ethanol (final volume of 20 ml) The resultant solution was cooled to10° C. and injected using an Ultrasonic Atomizer Nozzle at 60 Hz (20 μmdrop size, 10 mL/min), into 195 mL, of distilled water (37° C.). Ethanolwas removed from the resultant aqueous suspension of the micelle byrotary evaporation under a reduced pressure of 30 mm Hg to keep thetemperature of this solution below 30° C. The final volume of thissolution was 200 mL. To this solution was added 0.2 g, (0.1% w/v), guargum in 10 mg portions. The micelle formation efficiency using thismethod was >95%. The final maximum cannabinoid concentration was 2 g/Land micelles 50-200 nm in diameter were obtained. The aqueous micellesuspension was stable for 4 weeks at 25° C.

II. Liposome Formulation Example 5 50 g/L Liposomal Suspension of THC

TABLE 5 Micelle Formulation Ethanol Injection Lipid Amount 15 gramsEthanolic Soluable Soy Lecithin 50 Lipid Content Phosphatidylcholine(PC) ~52%, Phosphatidylethanolamine (PE) ~20%, Phospholipids (PPL) ~26%,other ~2% Drug Amount 15 grams Drug Source 70% THC content CannabisFlower Extract obtained from supercritical CO2 extraction. EthanolInjection 60 ml of 250 mg/ml THC, 130 mg/ml PC, 50 mg/ml PE, 65 mg/mlPPL in 95% Ethanol at 10° C. Injection Type 100 ml Syrnige w/ 22 gaugeneedle 50 psi 10 ml/min Aqueous Medium 540 ml Distilled H20 at 25° C.Final Ethanol to 1:10, ethanol and water removed via rotor Aqueous Ratioevaporation at 30 mmHg at less than 55 C. take to a final volume of 200ml Encapsulation >95% Efficiency Maximum final 200 mls of 50 g/l THCdrug concentration in suspension External None Stabilizer Micelldiameter 200-400 nm, aqueous core apparent under Characterisation oilimmersion, stable at RT for >3 months

15 g of a 70% THC cannabis flower extract obtained using supercriticalCO₂ extraction was dissolved in 95% ethanol (final volume of 30 ml).This ethanolic extraction solution was combined with an ethanolicsolution of Lecithin-50 (30 ml), which was prepared by dissolving 15grams of Lecithin-50 using small portions of 95% EtOH and bringing thefinal volume of the lipid/EtOH solution to 30 mL using 95% EtOH. Theethanolic solution of lipid and THC was cooled to 10° C. and injected ata pressure of 50 psi (10 mL/min), into 540 mL of distilled water (25°C.), using a 100 mL lurlock syringe equipped with a 22 gauge needle. Apressure of 50 psi, and a flow rate of 10 mL/min was maintained duringthe injection process. The liposomal suspension was concentrated to 200mL by rotary evaporation at 30 mm Hg keeping the temperature of theliposomal suspension below 55° C. The liposome formation efficiencyusing this protocol was greater than 95%. The final maximum THCconcentration was 50 g/L. Liposomes 200-400 nm in diameter were obtainedand had an aqueous core visible under oil immersion microscopy. Theaqueous liposomal suspension was stable for more than 3 months at 25° C.

The liposomes have a size of about 0.22 um, as determined by gelfiltration, and a spherical shape, as demonstrated by oil immersionlight microscopy (FIG. 2), and are unilamellar, as shown by freezefracture electron microscopy (data not shown). As shown in FIG. 3,staining with a cannabinoid specific dye (Fast Blue) demonstrated thatthe membrane, and not the core of the liposomes, stained with the dye.These data clearly demonstrated that the cannabinoid was entrapped inthe membrane and not in the core of the liposomes.

Example 6 50 g/L Liposomal Suspension of Pure Delta-9-THC

TABLE 6 Micelle Formulation Ethanol Injection Lipid Amount 10.5 gramsEthanolic Soluable Soy Lecitein 80 Lipid Content Phosphatidylcholine(PC) ~81%, Phosphatidylethanolamine (PH) ~7.5%, Phospholipids (PPL)~11%, other ~0.5% Drug Amount 10.5 grams Drug Source Drobabinol fromsigma (D9 THC) Ethanol Injection 40 ml of 262.5 mg/ml THC, 212 mg/ml PC,19.6 mg/ml PF, 28.8 mg/ml PPL in 95% Ethanol at 30° C. Injection Type0.17 mm stainless steel orifice at 10 ml/min at 300 psi Aqueous Medium360 ml Distilled H20 at 25° C. Final Ethanol to 1:10, ethanol and waterremoved via rotor Aqueous Ratio evaporation at 30 mmHg at less than 55C., take to a final volume of 200 ml Encapsulation >95% EfficiencyMaximum final drug 200 mls of 50 g/l THC concentration in suspensionExternal Stabilizer None Micell diameter 20-250 nm, aqueous coreapparent under Characterisation oil immersion, stable at RT for >3months

10.5 g of Dronobinol was dissolved in a portion of 95% ethanol (EtOH)and the final volume of this solution was brought to 20 ml using 95%EtOH. This ethanolic solution was combined with 20 ml of an ethanolicsolution of soluble soy lecithin-80 which was prepared by dissolving10.5 grams of Lecithin-80 into a portion of 95% EtOH and adjusting thevolume of the lipid/EtOH solution to 20 mL using 95% EtOH. The resultantsolution was cooled to 30° C. and injected through a 0.17 mm stainlesssteel orifice at 300 psi into 360 mL of distilled water (25° C.).Concentration of the ethanolic/aqueous liposomal suspension to 200 mL byrotary evaporation at 30 mm Hg to keep the temperature below 55° C. gavethe desired liposomal composition. The liposome formation efficiencywas >95% and the final concentration of THC was 50 g/L.

Liposomes 20-250 nm in diameter were obtained and had an aqueous corevisible under oil immersion microscopy. The aqueous liposomal suspensionwas stable for more than 3 months at 25° C.

Example 7 40 g/L Liposomal Suspension of a Mixture of Cannabinoids

TABLE 7 Micelle Formulation Ethanol Injection Lipid Amount 126 gramsEthanolic Soluable Soy Lecitein 80 Lipid Content Phosphatidylcholine(PC) ~81%, Phosphatidylethanolamine (PH) ~7.5%, Phospholipids (PPL)~11%, other ~0.5% Drug Amount 15.75 g THC, 7.875 g CBD, 7.875 g CBC DrugSource Synthsised In House Ethanol Injection 200 ml of 77.5 mg/ml THC,39.375 mg/ml CBD, 39.375 mg/ml CBC, 510 mg/ml PC, 47.25 mg/ml PF, 69.3mg/ml PPL in 95% Ethanol at 25° C. Injection Type Ultrasonic AtomizerNozzle @ 60 Hz, 20 um drop size, 10 ml/min Aqueous Medium 1.2 LDistilled H20 at 25° C. Final Ethanol 1:7, ethanol and water removed viarotor to Aqueous Ratio evaporation at 30 mmHg at less than 55 C., taketo a final volume of 500 ml Encapsulation >95% Efficiency Maximum finaldrug 750 mls of 21 g/l THC, 10 g/L CBD, 10 g/L CBC concentration insuspension External Stabilizer None Micell diameter 20-100 nm, aqueouscore apparent under Characterisation oil immersion, stable at RT for 24H

15.75 g of a 2:1:1 (w:w:w) ratio of THC, CBD, CBC were dissolved in aportion of 95% ethanol and brought to a final volume of 100 mL with 95%EtOH. This ethanolic solution was combined with an ethanolic solution ofsoluble soy Lecithin-80 (100 mL) which was prepared by dissolving 126 gof Lecithin-80 into a portion of 95% EtOH and bringing the volume of thelipid/EtOH solution to 100 mL. The resultant mixture was cooled to 25°C. and injected using an Ultrasonic Atomizer Nozzle at 60 Hz (20 μm dropsize, 10 mL/min), into 1.20 L of distilled water (25° C.). Theethanolic-aqueous liposomal suspension was concentrated by rotaryevaporation at 30 mm Hg and a temperature below 55° C. to a final volumeof 200 mL. The liposome formation efficiency was >95% and the finalmaximum concentration of THC was 40 g/L. Liposomes 20-100 nm in diameterand having an aqueous core visible under oil immersion microscopy wereobtained. The aqueous liposomal suspension was stable for more than 3months at 25° C.

III. Encapsulation Formulations Example 8 Calcium Alginate EncapsulatedLiposomal Suspensions of Cannabinoids

TABLE 8 Example 8: Encapulation of Liposomal suspension of Plant ExtractComponets Liposmal Suspension Source Example 5 Liposome DrugConcentration 50 g/L Encapulant Sodium Alginate EncapsulantConcentration 2% or 20 g/L Addition Method Bulk Addition CrosslinkingAgent CaCl2 Cross Linking agent concentration 40 mls of 25% CrosslinkingIncubation 10 mins Drying conditions Warm Air 50 C. for 24 H FinalProduct Description ~25 g Free Flowing Powder, disloves in buffered H20Content 10 g d9 THC, 10 g Lethicin 50, 4 g Alginate Active Drug Content~40% Release Profile 100% in 60 mM citrate pH 7.0

4 g of sodium alginate was dissolved in 200 mL of a 50 g/L liposomalsuspension (Example 5) of THC. The alginate/THC mixture was poured into40 mL of a stirring 25% aqueous solution of calcium chloride. Theresultant solution was further stirred for an additional 10 mins toallow crosslinking (polymerization) of alginic acid. The solid mass ofcalcium alginate encapsulated THC liposomal suspension is cold pressedto remove the majority of the water. The pressed material is furtherdried in warm air, 50° C., for 24 hrs. This air-dried material is milledto a free flowing yellowish white powder that readily dissolves inbuffered water. The cannabinoid content of the alginate powder is ˜40%,and the entrapped material is completely released in 60 mM, pH 7,citrate buffer.

Example 9 Film Formation of Liposomal Suspension

TABLE 9 Example 9: Film Formation of Liposomal suspension from pure D9THC Liposmal Suspension Source Example 6 Drug Concentration 50 g/LEncapulant Sodium Alginate or Agarose or Gelatin or pectin EncapsulantConcentration 4% or 40 g/L Crosslinking Agent none Cross Linking agentconcentration None Crosslinking Incubation None Drying conditions FreezeDrying or Spray Drying Final Product Description Free Flowing Powderdisloves in H20 Content 10 g d9 THC, 10 g Lethicin 50, 8 g Alginate (orother encapsulant) Active Drug Content ~20% Release Profile 100% indistilled H20

To the liposomal suspension prepared using the protocol of Example 6 wasadded sodium alginate in a amount sufficient to provide a 4% w/v (8grams) solution of alginate in liposomal suspension. The suspension isstirred at room temperature to dissolve the alginate. Once dissolved theentire suspension is shell frozen over a dry ice/acetone bath and freezedried to a solid mass which is milled to a free flowing powder. Yield 28grams. The powder thus obtained contains ˜40% cannabinoids and dissolvescompletely in distilled water.

Example 10 Calcium Alginate Encapsulated Liposomal Suspension of MixedCannabinoids

TABLE 10 Example 10: Encapsulation of Liposomal suspension of MixedCannabinoid Formulation Liposmal Suspension Source Example 7 DrugConcentration 21 g/L THC 10 g/L CBD, 10 g/L CBC Encapulant SodiumAlginate Encapsulant Concentration 4% or 20 g/L Addition MethodInjection through .17 um orfice 1 ml/min Crosslinking Agent CaCl2 CrossLinking agent 40 mls of 25% concentration Crosslinking Incubation 10mins Drying conditions Warm Air 50 C. for 24 H Final Product DescriptionFree Flowing Power, disloves in H20 Content 15.0 g d9 THC, 7.5 g CBD,7.5 g CBC, 120 g Lethicin 80, 15 g Alginate Active Drug Content ~9.5%THC, ~4.7% CBD, ~4.7% CBC Release Profile 100% in 60 mM citrate ph 7.0

To the liposomal suspension of mixed cannabinoids containing 15.0 g THC,7.5 g CBD, 7.5 g CBC and 120 g Lecithin-80 (Example 7), was added 4 g ofsodium alginate. The resultant solution was injected through a 0.17 mmstainless steel orifice at 300 psi into 40 mL of a stirring solution of25% aqueous calcium chloride. The resultant solution was further stirredfor an additional 10 mins to allow crosslinking (polymerization) ofalginic acid. The solid mass of calcium alginate encapsulated THCliposomal suspension is cold pressed to remove the majority of thewater. The pressed material is further dried in warm air, 50° C., for 24hrs. This air-dried material is milled to a free flowing yellowish whitepowder that readily dissolves in buffered water.

The cannabinoid content of the alginate powder is ˜9.5% THC, ˜4.7% CBD,˜4.7% CBC, and these compounds were completely released in 60 mM, pH 7,citrate buffer.

Example 11 Formation of a Dispersible Delta-9-THC Dry Powder

TABLE 11 Example 11: Dispersiable Dry Power D9 THC Liposmal PreparationLiposmal Suspension Source Example 6 Drug Concentration Diluted 1:10 to200 ml of 5 g/L Encapulant Lactose or Sucrose Encapsulant Concentration200 mg/ml Lactose or Sucrose, 0.6 mg/ml L-Lucine or IsolucineCrosslinking Agent none Cross Linking agent None concentrationCrosslinking Incubation None Drying conditions Spray Drying or FreezeDrying Final Product Description 42.5 grams white Free Flowing Powder,disloves in H20 Content 1 g d9 THC, 1 g Lethicin 50, 40 grams Lactose,0.12 L Lucine Active Drug Content ~2.3% Release Profile 100% indistilled H20

The liposomal preparation from Example 6 was diluted 1:10 with distilledwater. To 200 ml of the resulting solution was added lactose or sucrosein an amount sufficient to provide a 200 mg/ml (40 grams) solution ofthese reagents. L-lucine in an amount of 0.6 mg/ml (0.12 grams) was thenadded to the reaction mixture. The resultant solution was frozen using adry ice/acetone bath and freeze dried to obtain a solid mass.Alternatively the solution can be spray dried with a forced air spraydryer at a temperature of 55° C. The crystalline solid thus obtain wasmilled to a free flowing powder. Approximately 42 grams of resultingpowder containing approximately 1 g of THC, (i.e., a solid compositionhaving a cannabinoid content of ˜2.3%) was obtained. This powderdissolves completely in water releasing the liposomes. The resultingsuspension contains >90% of the starting liposomes.

What is claimed is:
 1. A method of producing a suspension of particlesof one or more cannabinoids in aqueous media consisting of the steps of:(a) dissolving one or more cannabinoids in ethanol to obtain an ethanolcannabinoid solution; (b) injecting the ethanol cannabinoid solutioninto distilled water; and (c) removing the ethanol from the compositionfrom step (b), thereby producing a suspension of particles of one ormore cannabinoids in aqueous media; (d) optionally adding stabilizerafter the ethanol has been removed; wherein the particles of one or morecannabinoids show no aqueous core under oil immersion microscopy.
 2. Themethod of claim 1, wherein the average particle diameter in the aqueouscannabinoid suspension is in a range between 50 and 1000 nm, and whereinthe concentration of cannabinoids in the aqueous cannabinoid suspensionis from about 1.0 g/liter to about 2 g/liter.
 3. The method of claim 1,wherein the one or more cannabinoids are selected from the groupconsisting of natural compounds, synthetic compounds, semi-syntheticcompounds, and mixtures thereof.
 4. The method of claim 3, wherein theone or more cannabinoids are selected from the group consisting ofcannabinol, cannabidiol, Δ9-tetrahydrocannabinol,Δ8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol,11-hydroxy-Δ9-tetrahydrocannabinol, levonatradol,Δ11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol,amandamide, nabilone, and combinations thereof.
 5. The method of claim 1wherein the stabilizer is present and is guar gum.
 6. A method ofproducing a suspension of particles of one or more cannabinoids inaqueous media consisting of the steps of: (a) providing plant materialfrom a cannabis plant; (b) subjecting the plant material from step (a)to supercritical fluid extraction to obtain an extract of cannabinoids;(c) dissolving the extract of step (b) in ethanol to obtain an ethanolcannabinoid solution; (d) injecting the ethanol cannabinoid solutioninto distilled water; and (e) removing the ethanol from the compositionfrom step (d), thereby producing a suspension of particles of one ormore cannabinoids in aqueous media; (f) optionally adding stabilizerafter the ethanol has been removed; wherein the particles of one or morecannabinoids show no aqueous core under oil immersion microscopy.
 7. Themethod of claim 6, wherein the average particle diameter in the aqueouscannabinoid suspension is in a range between 50 and 1000 nm, and whereinthe concentration of cannabinoids in the aqueous cannabinoid suspensionis from about 1.0 g/liter to about 2 g/liter.
 8. The method of claim 6wherein the stabilizer is present and is guar gum.